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Sex Differences in Antiretroviral Therapy Initiation in Pediatric HIV Infection
The incidence and severity of infections in childhood is typically greater in males. The basis for these observed sex differences is not well understood, and potentially may facilitate novel approaches to reducing disease from a range of conditions. We here investigated sex differences in HIV-infected children in relation to antiretroviral therapy (ART) initiation and post-treatment outcome. In a South African cohort of 2,101 HIV-infected children, we observed that absolute CD4+ count and CD4% were significantly higher in ART-naĂŻve female, compared to age-matched male, HIV-infected children. Absolute CD4 count and CD4% were also significantly higher in HIV-uninfected female versus male neonates. We next showed that significantly more male than female children were initiated on ART (47% female); and children not meeting criteria to start ART by >5yrs were more frequently female (59%; p<0.001). Among ART-treated children, immune reconstitution of CD4 T-cells was more rapid and more complete in female children, even after adjustment for pre-ART absolute CD4 count or CD4% (p=0.011, p=0.030, respectively). However, while ART was initiated as a result of meeting CD4 criteria less often in females (45%), ART initiation as a result of clinical disease in children whose CD4 counts were above treatment thresholds occurred more often in females (57%, p<0.001). The main sex difference in morbidity observed in children initiating ART above CD4 thresholds, above that of TB disease, was as a result of wasting and stunting observed in females with above-threshold CD4 counts (p=0.002). These findings suggest the possibility that optimal treatment of HIV-infected children might incorporate differential CD4 treatment thresholds for ART initiation according to sex
Indications for ART Initiation in 222 children whose CD4 counts were above CD4 treatment thresholds.
<p><sup>a</sup> Not within the guidelines for ART initiation in children</p><p>Indications for ART Initiation in 222 children whose CD4 counts were above CD4 treatment thresholds.</p
Proportion of HIV-infected children who were female in the subgroups analyzed within the Kimberley cohort.
<p>The proportion of female children in whom ART was initiated at CD4 counts higher than the CD4 thresholds compared to those in whom ART was initiated at CD4 counts lower than the CD4 thresholds differed significantly (p<0.001).</p
Multivariate analysis of sex differences in CD4+ T cell recovery after initiating ART.
<p><sup>a</sup> HR: Hazard ratio</p><p><sup>b</sup> 95% confidential interval range</p><p><sup>c</sup> aHR: adjusted hazard ratio</p><p>Multivariate analysis of sex differences in CD4+ T cell recovery after initiating ART.</p
Sex differences in immune reconstitution amongst the patients started treatment under the pre-2013 WHO guidelines.
<p>Sex differences by log rank test are shown as follows: A. Survival after ART initiation. B. CD4+ T cell percentage recovery (>35%) rate among the children who started ART aged 1–4 years old with CD4+ T cell <25%. C. Absolute CD4+ T cell count recovery (>750/ul) among children initiating ART aged ≥5 years old with absolute CD4+ T cell counts <350/ul.</p
Sex differences in CD4+ T cell count, CD4% and viral load, amongst 2,101 ART-naĂŻve South African children.
<p>A. Absolute CD4 counts changes with age. B. CD4% changes with age. C. Viral load changes with age. In each panel, the solid lines are Loess-smoothed regression lines for female children and the dotted lines are Loess-smoothed regression lines for male children. A multivariable linear regression model, with both sex and age as covariates, shows significantly lower absolute CD4 counts in males (p = 0.005); significantly lower CD4% in males (p = 3.7x10<sup>-7</sup>); and no significant difference in viral load between the sexes.</p
Absolute CD4 count, CD4% and viral load in HIV-infected children and HIV-uninfected neonates.
<p><sup><b>a</b></sup> Mann Whitney test</p><p><u>HIV-Infected Children, n = 2,101</u>.</p
Study cohorts of HIV-infected South African children analyzed.
<p>Study cohorts of HIV-infected South African children analyzed.</p